The present invention relates to an oral modified release pharmaceutical composition for the administration of a therapeutically and/or prophylactically effective amount of an active substance (a drug substance) to obtain a relatively fast or quick onset of the therapeutic and/or prophylactic effect. The drug substances contained in a modified release pharmaceutical composition according to the invention are suitably a drug substance which has a very low solubility under acidic conditions, i.e. under conditions similar to those present in the stomach and/or drug substances which have a pKa value below about 5.5 such as in a range of from about 4 to about 5. The compositions have been designed in such a manner that two important requirements are obtained, namely i) that the pharmaceutical composition releases the drug substance very fast under acidic conditions whereby the drug substance will become dissolved and, accordingly, available for absorption already almost immediately upon entrance into the stomach, and ii) that the mechanical strength of a composition according to the invention is sufficiently high to withstand normal handling of a pharmaceutical composition and to enable the composition to be coated using traditional coating equipment well known by a person skilled in the art. A composition according to the invention is suitable for use in those cases in which a fast onset of a therapeutic and/or prophylactic effect is desired, e.g. in connection with acute pain or mild to moderate pain. Accordingly, suitable therapeutically and/or propylactically active substances may inter alia be found in the class of drug substances denoted non-steroid anti-inflammatory drug substances (abbreviated in the following: NSAID substances or NSAIDs).
Pharmaceutical compositions designed to immediate release of a drug substance is known in the art.
Generally, however, the rationale which lies behind the kind of compositions which have been described to enable an immediate release of a drug substance is to employ a traditional formulation approach (such as, e.g., i) plain tablets which have a disintegration time in water of at the most about 30 min, ii) a traditionally formulated granulate or iii) loose powder of the drug substance itself. By doing so the immediate release part of the composition is intended to release the drug substance in a manner which corresponds to a plain tablet formulation or the like and the term xe2x80x9cimmediatexe2x80x9d is in such a context intended to denote that the release of the drug substance is faster than the release from a sustained release composition. The development of the so-called SplashDose(copyright), FlashDose(copyright) and Flashtabs(copyright) are examples of pharmaceutical compositions wherein the focus has been to obtain a very fast disintegration time. Such formulations are suitable for use for drug substances which are readily soluble in the gastrointestinal tract, but basically they do not solve the problems related to drug substances which have poor solubility characteristics.
Especially in those cases where the drug substance has a low solubility in an acidic medium having a pH of from about 1 to about 3, i.e. a pH corresponding to the pH in the stomach, the traditional formulation approach will lead to a pharmaceutical composition which has a suitable fast disintegration time but not necessarily a suitable fast dissolution rate of the drug substance under acidic conditions, i.e. a plain tablet will rapidly disintegrates into granules but the dissolution of the drug substance from the composition and/or the disintegrated composition under acidic conditions may be unsuitable low due to the solubility properties of the drug substance itself. The availability of a drug substance with respect to absorption, i.e. entrance into the circulatory system, is dependant on the presence of the drug substance on dissolved form as it is generally accepted that only dissolved substances are capable of passing the mucous membranes in the gastro-intestinal tract. Therefore, it is important that the dissolution of the drug substance is suitably fast even under acidic conditions in order to enable a fast and initial absorption so that a true fast or immediate therapeutic response is obtainable.
For drug substances which are weak acids it is very important to ensure a proper bioavailability of the drug substance already under acid conditions in order to achieve a true rapid therapeutic effect. However, the various approaches disclosed with respect to achievement of a combination of a rapid effect do not seem to take all the above-mentioned factors into account and, hence, there is a need for developing compositions which enable a true rapid onset of the therapeutic effect. To this end, we have especially focused on compositions comprising a drug substance belonging to the class of drug substances normally denoted NSAIDs, but other drug substances having a low solubility in acidic medium and/or a pKa below about 5.5 may as well be suitable for use in a composition according to the invention.
Moreover, patients suffering from acute pain, mild to moderate pain and/or inflammatory conditions and/or related conditions very often require a dosage and a formulation which enable a fast onset of the therapeutic effect of the NSAID substances. The release from the dosage form must be safe, predictable and reliable. Furthermore, from a technical point of view, the release rate and the release pattern of the active drug substance from the composition should not significantly change during the shelf-life of the composition. A change in the release rate and/or release pattern may have a significant impact on the in vivo performance of the composition.
When testing prior art compositions intended for rapid release of the active drug substance (see e.g. Japanese patent No. 33491/90) the present inventors have revealed problems with respect to the release rate obtained and the robustness of the tablets. Thus, the development of a pharmaceutical composition which is suitable for rapid release of the active substance seems surprisingly to be a balance of on the one hand to obtain a composition which is sufficient robust to withstand normal handling (i.e. to have a sufficient mechanical strength) and on the other hand to enable a fast release and dissolution of the active drug substance in an acidic aqueous medium.
Thus, the purpose of the present invention is to provide a pharmaceutical composition for oral use which is useful for a fast delivery of an active drug substance to the circulatory system upon administration.
In one aspect, the invention relates to a quick release pharmaceutical composition for oral administration comprising a therapeutically and/or prophylactically active substance which has a solubility of at the most about 0.1% w/v in 0.1 N hydrochloric acid at room temperature,
the composition being based on a powder comprising the therapeutically and/or prophylactically active substance and having such a particle size thatxe2x80x94when the powder is subjected to a sieve analysisxe2x80x94then at least about 90% w/w such as, e.g. at least about 92% w/w, at least about 94% w/w, at least about 95% w/w, at least about 96% w/w, at least about 97% w/w, at least about 97% w/w, at least about 98% w/w or at least about 99% w/w of the particles passes through sieve 180 xcexcm, the powder being contacted with an aqueous medium to form a particulate composition, which has such a particle size thatxe2x80x94when the particulate composition is subjected to a sieve analysisxe2x80x94then at least about 50% w/w such as, e.g., at least about 55% w/w, at least about 60% w/w, at least about 65% w/w, at least about 70% w/w, at least about 75% w/w, at least about 80% w/w, at least about 85% w/w, at least about 90% w/w or at least about 95% w/w of the particles passes through sieve 180 xcexcm, and
the compositionxe2x80x94when tested in accordance with the dissolution method I defined herein employing 0.07 N hydrochloric acid as dissolution mediumxe2x80x94releases at least about 50% w/w of the active substance within the first 20 min of the test.
In another aspect the invention relates to a quick release pharmaceutical composition for oral administration comprising a therapeutically and/or prophylactically active substance which has a solubility of at the most 0.1% w/v in 0.1 N hydrochloric acid at room temperature,
the composition being in the form of a particulate composition or being based on a particulate composition which is obtained by contacting a powder comprising the therapeutically and/or prophylactically active substance with an aqueous medium in such a manner that the mean particle size of the particles of the particulate composition is at the most about 100% larger than the mean particle size of the powder before contact with the aqueous medium, and
the compositionxe2x80x94when tested in accordance with the dissolution method I defined herein employing 0.07 N hydrochloric acid as dissolution mediumxe2x80x94releases at least about 50% w/w of the active substance within the first 20 min of the test.
In preferred embodiments, the composition releases at least 55% w/w such as, e.g., at least about 60% w/w, at least about 65% w/w, at least about 70% w/w, at least about 75% w/w, at least about 80% w/w, at least about 85% w/w, at least about 90% w/w, at least about 95% w/w, at least about 96% w/w, at least about 97% w/w, at least about 98% w/w or at least about 99% w/w of the total active drug substance present in the composition within the first 20 min of the test.
In another aspect the invention relates to a method for the preparation of a composition according to the invention, the method comprising the steps of
i) mixing the therapeutically and/or prophylactically active substance with a) an alkaline substance, b) a filler having binding properties, and, optionally, c) other pharmaceutically acceptable excipients to obtain a powder mixture,
ii) contacting the thus obtained powder mixture with an aqueous medium to obtain a wet powder,
iii) drying the thus obtained wet powder at a temperature above room temperature until the water content in the powder is at the most about 5% w/w determined as described herein, to obtain a first particulate mixture,
iv) sieving the thus obtained first particulate mixture,
v) optionally, adding any further pharmaceutically acceptable excipients to obtain a second particulate mixture,
vi) optionally, compressing the thus obtained second particulate mixture into tablets, and
vii) optionally, coating the thus obtained tablets.
In still further aspects the invention relates to a method for treatment and/or prophylaxis of acute pain and/or mild or moderate pain comprising administering to a patient an effective amount of a therapeutically and/or prophylactically active drug substance in the form a quick release composition according to the invention.
As mentioned above, the solubility of the therapeutically and/or prophylactically active substance in 0.1 N hydrochloric acid at room temperature is at the most about 0.1% w/v such as, e.g., at the most about 0.05% w/v, at the most about 0.01% w/v, at the most about 0.009% w/v, at the most about 0.008% w/v, at the most about 0.007% w/v, at the most about 0.006% w/v, at the most about 0,005% w/v, at the most about 0,004% w/v, at the most about 0.003% w/v, at the most about 0.002% w/v or at the most about 0.001% w/v.
Since the solubility of the therapeutically and/or prophylactically active substance such as, e.g., lornoxicam is  less than 1 mg/100 ml in 0.1 N HCl (aqueous solution of 0.1 N hydrochloric acid) the present inventors have found that incorporation of e.g. an NSAID substance in free form or in the form of a traditional formulation does not give the desired quick release under acidic conditions to enable a fast onset of the therapeutic effect in vivo.
Furthermore, irrespective of the solubility under acidic conditions, a composition containing an active drug substance which has a very low dissolution rate in 0.1 N or 0.07 N HCl may also present problems with respect to obtaining a quick release and dissolution of the active drug substance. Accordingly, compositions according to the invention may as well contain a therapeutically and/or prophylactically active substance whichxe2x80x94when tested by solubility method I described hereinxe2x80x94has such a dissolution rate that it allows an amount of at the most 50% w/w of the active substance to be dissolved within the first 20 min of the test.
A quick release of an active drug substance (such as, e.g., an NSAID substance) will, however, take place under acidic conditions provided that the drug substance is presented in a formulation wherein specific means has been used in order to manipulate the release rate so that the release becomes much faster compared to a traditional composition. Thus, the present inventors have found it necessary to adjust the release rate from a traditional composition when the active drug substance either has i) a very low solubility in 0.1 N hydrochloric acid, ii) a very low solubility rate, or iii) has a pKa below about 5.5 such as, e.g., at the most about 5.3, at the most about 5.2, at the most about 5.0 such as, e.g., in a range of from about 3.4 to about 5.0, in a range of from about 4.0 to about 5.0. Thus, a fast release composition must be manipulated with respect to release in order to achieve a suitable fast release rate.
The present inventors have surprisingly found that in order to obtain a quick release composition containing active drug substances like the ones described above it is necessary to subject the active drug substance to contact with an alkaline substance under certain conditions. Furthermore, the success of the manufacture, i.e. a tablet that fulfils the general requirements of tablets, depends not only on a sole addition of e.g. sodium hydrogencarbonate (as described in Japanese patent No. 33491/90, Taisho) but also on the following parameters:
1. Contact conditions for the active drug substance and an alkaline substance (contact time, energy input and contact medium)
2. Inclusion of a substance denoted xe2x80x9ca filler having binding propertiesxe2x80x9d
3. The mean particle size of the filler having binding properties
4. The mean particle size or the particle size (as obtained from a sieve analysis) of the particulate material obtained after contacting the active drug substance and the alkaline substance with an aqueous medium and before any manufacture of the composition into e.g. tablets
5. The porosity of the particles obtained after contacting the active drug substance and the alkaline substance with an aqueous medium and before any manufacture of the composition into e.g. tablets. The present inventors have found that in certain cases it is possible to obtain suitable release characteristics even if the particle size is not as small as claimed. In those cases, however, the porosity of the particles has been sufficiently high to allow a quick release or alternatively, the hardness of the particles is low.
In the experimental section herein is shown the influence of various process parameters on the properties of the resulting composition. The overall conclusion from the experiments is that in order to obtain a quick release composition it is of utmost importance to control conditions under which the contact between the active drug substance and the alkaline substance takes place. Furthermore, it is demonstrated that in order to obtain a composition with favourable shelf-life it seems necessary that the contact takes place during the manufacturing of the composition (see Example 12 which shows that when the contact between the active drug substance and the alkaline substance has taken place before manufacturing then a decreased shelf-life is obtained). Further investigations have shown that a suitable release is only obtained when the particle size of the particulate material obtained after contact between the active drug substance and the alkaline substance is controlled. (However, as explained above, the particle size requirement can be less stringent if the porosity of the particulate material is increased or if the hardness of the particles is decreased) In other words, it is of utmost importance with respect to the release of the active substance to ensure that the contact in situ between the active drug substance and the alkaline substance takes place under controlled conditions. The contact is performed by adding an aqueous medium to a powder mixture comprising the active drug substance and the alkaline substance and, optionally the filler having binding properties and other pharmaceutically acceptable excipients. The addition of such a medium is performed by the same procedures as if the powder mixture is subjected to a wet granulation process. However, the present inventors have found that the application of the aqueous medium and the process involved must be controlled in such a manner that the resulting particulate mixture is not a traditional granulate, i.e. agglomerates built up of particles of the substances employed. Normally, during a granulation process the particle size is increased by a factor of at least 1.5 and a 200-500% increase may be observed. However, if agglomerates are formed to a major extent, the mean particle size of the particulate mixture will become so large that it has a negative impact on the release rate.
Furthermore, the constitution of the aqueous medium is an important and critical factor (see below).
As a consequence of the above-mentioned formulation requirements, the present inventors have found that the manufacture of a composition according to the inventionxe2x80x94even if a wetting step is includedxe2x80x94is to be regarded as a process suitable for dry granulation and/or dry compression. It is contemplated that the balance between the qualities of the excipients and the aqueous treatment of the active substance and the alkaline substance is very important in order to obtain a suitable result with respect to both obtaining a quick release and a proper, substantially robust composition. It is believed that a mere effervescent tablet containing e.g. the active substance and sodium hydrogen carbonate will not lead to a controlled quick release because the carbon dioxide formed when such a tablet is dissolved in a glass of water will lead to a quick disintegration but not a quick dissolution. Most likely, the disintegration is so quick that the individual components (e.g. the active substance and the alkaline substance) have no substantial influence on one another. By subjecting the active substance and the alkaline substance to a controlled aqueous treatment, the formation of carbon dioxide during this treatment is believed to take place to some extent but the gas formation is not exhausted. Thus, when the tablet disintegrates in the stomach the remaining carbon dioxide is formed which allows a more ideal disintegration of the tablet and, consequently, gives rise to a local condition in the stomach which is favourable for quick dissolution of the active substance. A local increase in the pH value in the microenvironment of the particles is thus contemplated.
A composition according to the invention may be in the form of a solid composition such as in the form of a particulate composition or in the form of a unit dosage composition such as, e.g., a tablet, a capsule, a sachet or the like.
As mentioned above, the process with respect to the preparation of a composition according to the invention has to be controlled. Thus, it is important that the active drug substance is brought into contact with an alkaline substance. The alkaline substance may be an antacid or an antacid-like substance such as, e.g., sodium hydrogen carbonate, sodium carbonate, potassium carbonate, magnesium carbonate, magnesium hydroxide or magnesium metasilicate aluminate or mixtures thereof. The reaction medium is typically a solvent comprising water and an organic solvent. The organic solvent is a solvent which is miscible with water such as, e.g., a branched or unbranched lower (C1-C5) aliphatic alcohol like, e.g., ethanol, methanol, isopropanol, 1-propanol, 1-butanol, 2-butanol, tert. butanol 1-pentanol, 2-pentanol, 3-pentanol, iso-pentanol and tert. pentanol and mixtures thereof.
The concentration of the organic solvent in the solvent employed is normally from about 0% v/v to about 95% v/v such as, e.g., from about 10% v/v to about 90% v/v, from about 10% v/v to about 80% v/v, from about 15% v/v to about 70% v/v, from about 15% v/v to about 60% v/v, from about 20% v/v to about 50% v/v, from about 20% v/v to about 40% v/v, from about 25% v/v to about 30% v/v such as, e.g. about 25% v/v.
An especially suitable organic solvent is ethanol in a concentration from about 0% v/v to about 95% v/v. The present inventors have found that a contact medium, i.e. an aqueous medium, comprising water and ethanol in a volume ratio of from about 1:50 to about 1:1 is suitable, preferably the ratio is from about 1:10 to about 1:1 such as, e.g. 1:2 or 1:3. Such an aqueous medium may only contain water and ethanol or it may contain other solvents as well.
The contact is generally carried out without any external heating, but of course heating may be employed to speed up the process. The contact performed may result in a formation of a conjugate, an adduct or a salt or a partial salt but investigations are on-going in order to clarify this specific question. Without being limited in any way, it is presently believed that the conjugate or adduct formed may be in the form of a salt or complex formed by a reaction between the therapeutically and/or prophylactically active substance and the alkaline substance employed in process step i) above.
If the active drug substance and the alkaline substance is processed under conditions where an aqueous contact between the two components does not take place (i.e. under anhydrous conditions) then the present inventors have found that the resulting composition does not fulfil the requirements herein with respect to the release the active drug substance from the composition.
The mean particle size of the antacid-like substance employed in compositions according to the invention (as raw material) is normally at the most about 250 xcexcm, such as at the most about 225 xcexcm, at the most about 200 xcexcm, at the most about 175 xcexcm, at the most about 150 xcexcm, at the most about 145 xcexcm, at the most about 140 xcexcm, at the most about 135 xcexcm, at the most about 130 xcexcm such as, e.g., in a range of from about 20 xcexcm to about 250 xcexcm, in a range of from about 40 xcexcm to about 200 xcexcm, in a range of from about 60 xcexcm to about 175 xcexcm, in a range from about 80 xcexcm to about 150 xcexcm or in a range of from about 100 xcexcm to about 120 xcexcm.
Besides the employment of an alkaline substance in order to enable a suitable contact with the active drug substance, another important ingredient in a composition according to the invention is an ingredient which imparts the necessary mechanical strength to the composition to enable normal handling and, optionally, conventional coating of the composition. In the present context, such an ingredient is denoted xe2x80x9ca filler having binding propertiesxe2x80x9d. As demonstrated in the Examples herein compositions without such an ingredient or compositions including such an ingredient but having an inappropriate particle size seem to be compositions which are too soft, i.e. have such a poor mechanical strength (friability and crushing strength) that they will not withstand the handling tablets normally have to withstand in order to be used by patients.
Examples of a suitable filler having binding properties for use in compositions according to the invention is, e.g., lactose (such as, e.g., Tabletose(copyright), Pharmatose(copyright)), sugar derivatives (such as, e.g., mannitol, sorbitol), calcium carbonate (CaCO3), tricalcium phosphate (Ca5(PO4)3OH), calcium hydrogen phosphate (CaHPO4) (such as, e.g., Di-Cafos(copyright), Di-Tab(copyright), Emcompress(copyright) or Pharmacompress(copyright)), or the like and/or mixtures thereof.
In the experimental section herein calcium hydrogen phosphate has been employed as an example of a filler having binding properties and the results show that the mechanical strength of the tablets prepared is dependant on the particle size of the calcium hydrogen phosphate employed. Too small or too large a particle size will result in tablets which are too soft to withstand normal handling by patients.
Accordingly, the filler having binding properties as raw material has normally a mean particle size of at the most about 140 xcexcm, such as, e.g., at the most about 130 xcexcm, at the most about 120 xcexcm, at the most about 110 xcexcm, at the most about 100 xcexcm, at the most about 90 xcexcm, at the most about 80 xcexcm, at the most about 70 xcexcm, at the most about 60 xcexcm, at the most about 50 xcexcm, at the most about 40 xcexcm, at the most about 35 xcexcm, at the most about 30 xcexcm or at the most about 25 xcexcm such as, e.g., in a range of from about 10 xcexcm to about 80 xcexcm, or in a range of from about 10 to about 65 xcexcm such as e.g. 15-55 xcexcm.
In accordance with the discussion above relating to the particle size, the process step ii) above in a process for the preparation of a composition according to the invention is performed in a conventional high shear mixer employing an energy input which is sufficient to enable a contact to take place between the therapeutically and/or prophylactically active substance and the alkaline substance employed in step i) but at the same time is sufficiently low to avoid formation of a large amount of agglomerates during the mixing.
Thus, in a composition according to the invention, the mean particle size of the particles of the particulate mixture obtained after contact between the active drug substance and the alkaline substance (including any other ingredients present such as, e.g. a filler having binding properties) is at the most about 100% larger than the mean particle size of the powder mixture before the reaction in an aqueous medium. More specifically, the mean particle size of the particle of the particulate composition is at the most 90% such as, e.g., about 80%, about 75%, about 70%, about 65%, about 60%, about 55% or about 50% larger than the mean particle size of the powder mixture before the reaction in an aqueous medium.
The particle size of the particulate mixture is also expressed by means of results obtained from a sieve analysis, namely that at least about 50% w/w such as, e.g., at least about 55% w/w, at least about 60% w/w, at least about 65% w/w, at least about 70% w/w, at least about 75% w/w, at least about 80% w/w, at least about 85% w/w, at least about 90% w/w or at least about 95% w/w of the particles passes through sieve 180 xcexcm. Before the contact with the aqueous medium, the particle size of the powder is also expressed by means of results obtained from a sieve analysis, namely that at least about 90% w/w such as, e.g. at least about 92% w/w, at least about 94% w/w, at least about 95% w/w, at least about 96% w/w, at least about 97% w/w, at least about 97% w/w, at least about 98% w/w or at least about 99% w/w of the particles passes through sieve 180 xcexcm.
With respect to the mean particle size of the particles of the particulate composition obtained after contact of between the active drug substance with the alkaline substance (including any other ingredients present such as, e.g. a filler having binding properties) it is at the most about 250 xcexcm, such as, e.g. at the most about 240 xcexcm, at the most about 230 xcexcm, at the most about 220 xcexcm, at the most about 210 xcexcm, at the most about 200 xcexcm, at the most about 190 xcexcm, at the most about 180 xcexcm, at the most about 175 xcexcm, at the most about 150 xcexcm, at the most about 125 xcexcm, at the most about 100 xcexcm, at the most about 90 xcexcm, at the most about 80 xcexcm or at the most about 75 xcexcm, whenever appropriate, after a reaction in an aqueous medium.
As mentioned above, a composition according to the invention has such a mechanical strength that it can be subjected to normal handling and coating in conventional coating apparatus without breakage or otherwise rupture. Therefore, a composition according to the invention in the form of tablets having a diameter of 9.5 mmxe2x80x94when subjected to a crushing strength test in accordance with Ph. Eur.xe2x80x94has a crushing strength of at least about 50 N such as, e.g., at least about 60 N, at least about 70 N, at least about 80 N such as, e.g., in a range from about 60 to about 130 N, in a range from about 70 to about 120 N or in a range of from about 75 to about 110 N such as from about 80 to about 100 N. With respect to tablets having other diameters than 9.5 mm, a person skilled in the art will know which crushing strength values become relevant.
An important ingredient with respect to imparting the desired mechanical strength to a composition according to the invention (if the composition is in the form of a tablet) is as mentioned above the filler having binding properties. Therefore, a composition according to the inventionxe2x80x94when tested as a composition without the filler having binding properties in the crushing strength apparatus according to Ph. Eur.xe2x80x94is contemplated to have a crushing strength of less than about 45 N such as, e.g., less than about 30 N, less than about 25 N, less than about 20 N, less than about 15 N or less than about 10 N.
In order i) to avoid any substantial degradation of the active drug substance employed in a composition according to the invention and ii) to enable a substantially constant release rate of the active drug substance from a composition according to the invention in the life span of the composition, water content in the composition is at the most about 5% w/w such as, e.g., at the most about 4% w/w, at the most about 3%, at the most about 2% w/w, at the most about 1.5% w/w, at the most about 1.3% w/w, at the most about 1.1% w/w, at the most about 1.0% w/w or at the most about 0.9% w/w determined by a LOD (loss on drying) method (IR dryer, 30 min at 70xc2x0 C.).
Definitions of Selected Terms Used Herein
The term xe2x80x9cmodified release compositionxe2x80x9d used in the present context is defined as a composition from which the release of the drug differs from that of a traditional composition. The release rate is in other words controlled and it is possible to manipulate the release rate by e.g. changing the formulation parameters. The term xe2x80x9cmodifiedxe2x80x9d is often used in the sense of prolonged, but the term is not restricted to an extended or prolonged effect; the term xe2x80x9cmodifiedxe2x80x9d may as well cover the situation where the release rate is manipulated in such a manner that a quicker release than normally expected is obtained. Thus, in the present context the terms xe2x80x9cquickxe2x80x9d, xe2x80x9cfastxe2x80x9d and xe2x80x9cenhancedxe2x80x9d release as well as xe2x80x9ccontrolledxe2x80x9d, xe2x80x9cdelayedxe2x80x9d, xe2x80x9csustainedxe2x80x9d, prolongedxe2x80x9d, xe2x80x9cextendedxe2x80x9d and other synonyms well known to a person skilled in the art are covered by the term xe2x80x9cmodifiedxe2x80x9d, but with respect to the present invention, the term xe2x80x9cmodified releasexe2x80x9d is to be understood as a xe2x80x9cquick releasexe2x80x9d, xe2x80x9cfast releasexe2x80x9d or xe2x80x9cenhanced releasexe2x80x9d.
The term modified release in the present context refers to a composition which can be coated or uncoated and prepared by using pharmaceutically acceptable excipients and/or specific procedures which separately or together are designed to modify the rate or the place at which the active ingredient or ingredients are released (Ph. Eur. 97).
The terms xe2x80x9cquick releasexe2x80x9d, xe2x80x9cfast releasexe2x80x9d or xe2x80x9cenhanced releasexe2x80x9d in the present context refer to a modified release composition of which the release of the active ingredient and its subsequent absorption are fast. More specifically, the terms xe2x80x9cquick releasexe2x80x9d, xe2x80x9cfast releasexe2x80x9d or xe2x80x9cenhanced releasexe2x80x9d mean that for a compositionxe2x80x94when subjected to a dissolution method I described hereinxe2x80x94at least about 50% w/w of the active substance is dissolved within the first 20 min of the test.
The term xe2x80x9cdosage unitxe2x80x9d in the present context refers to one single unit, e.g. a capsule, tablet, a sachet or any other relevant dosage form known within the art. A dosage unit may represent a plurality of individual units which in accordance with the general state of the art may be in the form of a capsule, a tablet, a sachet, etc.
The term xe2x80x9cbioavailabilityxe2x80x9d designates the rate and extent to which the drug is absorbed from the modified release composition.
The terms xe2x80x9cNSAIDsxe2x80x9d or xe2x80x9cNSAID substancesxe2x80x9d are used herein to designate a group of drugs that belongs to non-steroid anti-inflammatory drug substances and pharmaceutically acceptable salts, prodrugs and/or complexes thereof as well as mixtures thereof.
The therapeutic classes mentioned herein are in accordance with the ATC (Anatomical Therapeutic Chemical) classification system.
Active Drug Substances
In the following are given examples of active drug substances which may be incorporated in a composition according to the invention. A majority of the active drug substances mentioned are weak acids, i.e. substances which have a pKa value below about 5.5 such as, e.g., in a range of from about 3.0 to about 5.5 or in a range of from about 4.0 to about 5.0. In this connection it can be mentioned that the pKa value for lornoxicam is about 4.7, for naproxen about 4.2, for indometacin about 4.5 and for acetylsalicylic acid about 3.5. Moreover, active drug substances like those mentioned above (i.e. weak acids having a pKa value of at the most about 5.5 or about 5.0) generally have a poor solubility in media having a pH below the pKa value; as an example the solubility of lornoxicam at a pH corresponding to 0.1 N HCl is less than about 1 mg/100 ml at room temperature and active drug substances like acetylsalicylic acid, indometacin and naproxen are regarded as substances which are practically insoluble in water and 0.1 N HCl at room temperature. From the discussion relating to solubility and availability of the active drug substance in order to get access to the circulatory system it is should be appreciated that the release (dissolution) of the active drug substance from the composition should be quick under acidic conditions, e.g., in 0.1 N HCl even if the active drug substance has a very low solubility in this medium.
Relevant examples of active drug substances suitable for use in compositions according to the invention are in general weakly acidic substances such as, e.g., paracetamol and/or NSAID substances like
aminoarylcarboxylic acid derivatives like e. g. enfenamic acid, flufenamic acid, isonixin, meclofenamic acid, mefenamic acid, morniflumate, niflumic acid, and tolfenamic acid,
arylacetic acid derivatives like e.g. aceclofenac, acemetacin, amfenac, bromfenac, cimmetacin, diclofenac, etodolac, fentiazac, glucametacin, indomethacin, lonazolac, metiavinic acid, oxametacine, pirazolac, proglumetacin, sulindac, tiaramide, tolmetin, and zomepirac,
arylcarboxylic acids like e.g. ketorolac and tinoridine,
arylpropionic acid derivatives like e. g. alminoprofen, bermoprofen, carprofen, dexibuprofen, fenbufen, fenoprofen, flunoxaprofen, flurbiprofen, ibuprofen, ibuproxam, ketoprofen, loxoprofen, naproxen, oxaprozin, pranoprofen, protizinic acid, and tiaprofenic acid,
pyrazoles like e.g. epirizole,
pyrazolones like e.g. benzpiperylon, mofebutazone, oxyphenbutazone, phenylbutazone, and ramifenazone,
salicylic acid derivatives like e.g. acetaminosalol, acetylsalicylic acid, benorylate, eterisalate, fendosal, imidazole salicylate, lysine acetylsalicylate, morpholine salicylate, parsalmide, salamidacetic acid and salsalate,
thiazinecarboxamides like a.o. ampiroxicam, droxicam, lornoxicam, meloxicam, piroxicam, and tenoxicam,
others like bucillamine, bucolome, bumadizon, diferenpiramide, ditazol, emorfazone, nabumetone, nimesulide, proquazone and piroxicam (e.g. in the form of a betacyclodextrin complex).
From a market point especially the following NSAIDs are interesting: lornoxicam, diclofenac, nimesulide, ibuprofen, piroxicam, piroxicam (betacyclodextrin), naproxen, ketoprofen, tenoxicam, aceclofenac, indometacin, nabumetone, acemetacin, morniflumate, meloxicam, flurbiprofen, tiaprofenic acid, proglumetacin, mefenamic acid, fenbufen, etodolac, tolfenamic acid, sulindac, phenylbutazone, fenoprofen, tolmetin, acetylsalicylic acid, dexibuprofen and pharmaceutically acceptable salts, complexes and/or prodrugs and mixtures thereof.
Other relevant active drug substances are COX-2 (COX is an abbreviation for cyclooxygenase) inhibitors like e.g. celecosib and flosulide.
At present, the most preferred drug substance is lornoxicam and pharmaceutically acceptable salts, complexes and prodrugs thereof. Lornoxicam may be present in a composition according to the invention as the sole drug substance or in combination with other drug substances.
In those cases where a quick release composition of the present invention includes an NSAID substance as the therapeutically active ingredient, the amount of the active drug substance corresponds to from 1 to about 1600 mg of by weight. Alternatively, the dosage form may contain molar equivalent amounts of pharmaceutically acceptable salts thereof. The dosage form contains an appropriate amount to provide a substantially equivalent therapeutic effect.
The active substances mentioned above may be present in a composition according to the invention as i) the only drug substance, or ii) together with at least one other active drug substance such as, e.g. an NSAID substance.
Relevant substances in this context are e.g. antidepressants, opioids, prostaglandine analogs (e.g. misoprostol), glucocorticosteroids, cytostatics (e.g. methotrexate), H2 receptor antagonists (e.g. cimetidine, ranitidine), proton pump inhibitors (e.g. pantoprazole, omeprazole, lansoprazole), antacids, furosemid, acetaminophen (paracetamol), penicillamine, sulfasalazine and/or auranorfin, andxe2x80x94whenever relevantxe2x80x94pharmaceutically acceptable salts, complexes and/or prodrugs and mixtures thereof.
The term xe2x80x9cantidepressantxe2x80x9d used in the present context includes tricyclic antidepressants as well as other antidepressants and mixtures thereof. Pharmaceutically acceptable salts and/or complexes of antidepressant are also within the definition of antidepressant. Thus, the term xe2x80x9cantidepressantxe2x80x9d is used here to designate a group of drugs that have, to varying degrees, antidepressive properties and/or suitable properties with respect to alleviation or treatment of neurogenic pain and/or phantom pain. In the present context the term xe2x80x9cantidepressantxe2x80x9d encompasses drug substances mainly from the therapeutic class N06 or from the following drug classification: Psychoanaleptics excluding anti-obesity preparations; anti-depressants/thymoanaleptics including substances used in the treatment of endogenous and exogenous depression such as, e.g., imipramine, nortriptyline, amitriptyline, oxipramol and MAO-inhibiting substances; lithium; combinations of drugs with ataractics; psychostimulants including drugs which increase the psychic and physical performance and which have a fatigue depressing, stimulating effect such as, e.g., fentyllines, fencamfamine, methyiphenidate, amphetamines; pyscholeptic-psychoanaleptic combinations; nootropics [which are a class of psychoactive drugs which are claimed to have a selective action on integrative functions of the CNS. Their action is alleged to be particularly associated with intellectual function, learning and memory. Nootropics include preparations containing substances such as piracetam, pyritinol, pyrisuccideanol maleate, meclofenoxate, cyprodenate and their combinations with other substances, excluding those products with a vasodilatory action (see the therapeutic class C04A). Combinations with cardiac glycosides are classified in the therapeutic class C01A]; and neurotonics and other miscellaneous products including products which are not classified above such as single or combination products containing bisibutiamin, deanol and derivatives, GABA, GABOB, N-acetyl asparaginic acid glutaminic acid and salts, kavain, phospholipid, succinodinitrate.
The presently most interesting drug substances belong to the tricyclic antidepressants. Relevant examples of antidepressants are: tricyclic antidepressants such as, e.g. dibenzazepine derivatives like carpipramine, clomipramine, desipramine, imipramine, imipraminoxide, imipramine pamoate, lofepramine, metapramine, opipramol, quinupramine, trimipramine; dibenzocycloheptene derivatives like amitriptyline, amitriptyline and chlordiazepoxide, amitriptyline and medazepram, amitriptyline and pridinol, amitriptyline and perphenazine, amitriptylinoxide, butriptyline, cyclobenzaprine, demexiptiline, nortriptyline, nortriptyline and diazepam, nortriptyline and perphenazine, nortriptyline and fluphenazine, nortriptyline and flupentixol, noxiptilin, protriptyline; dibenzoxepine derivatives like doxepin; and other tricyclic anti-depressants like adinazolam, amoxapine, dibenzepin, dimetacrine, dosulepin, dosulepin and diazepam, dothiepin, fluacizine (fluoracyzine, toracizin), iprindole, maprotiline, melitracen, melitracene and flupentixol, pizotyline, propizepine, and tianeptine; other antidepressants like 5-hydroxytryptophan, ademetionine, amfebutamone, amfebutamone hydrochloride, amineptine, amineptine hydrochloride, amisulpride, fluoxetine hydrochloride, fluoxetine, hypericin, lithium carbonate, sertraline hydrochloride, sertraline, St John""s wort dry extract, trimipramine maleate, citalopram, citalopram hydrobromide, clomipramine chloride, clomipramine hydrochloride, d-phenylalanine, demexiptiline, demexiptiline hydrochloride, dimethacrine tartrate, dothiepin, dothiepin hydrochloride, doxepin, fluphenazine hydrochloride, fluvoxamine, fluvoxamine hydrogen maleate, fluvoxamine maleate, ginkgo biloba, indalpine, isocarboxazide, johanniskrauttrockenestrakt, 1-tryptophan, lithium citrate, lithium sulfate, lofepramine, maprotiline, maprotiline hydrochloride, maprotiline mesilate, medifoxamine, metaprimine fumarate, mianserin, moclobemide, nitroxazepine hydrochloride, nomifensine, nomifensine maleate, nomifensin hydrogenmaleat, oxitriptan, paroxetine, paraoxetine hydrochloride, pheneizine, pheneizine sulfate, piracetam, pirlindole, pivagabine, prolintane hydrochloride, propizepine hydrochloride, protriptyline hydrochloride, quinupramine, remoxipride hydrochloride, rubidium chloride, setiptiline maleate, tianeptine sodium, trazodone hydrochloride, venlafaxine hydrochloride, maprotiline, toloxatone, tranylcypromine, trazodone, trazodone hydrochloride, viloxazine, viloxazine hydrochloride, zimelidine, zimelidine dihydrochloride.
At present, the most interesting antidepressant drug substances for use in a composition according to the invention are amitriptyline and/or imipramine and pharmaceutically acceptable salts, complexes and prodrugs thereof. Amitriptyline and/or imipramine may be present in a composition according to the present invention either as the sole drug substance or in combination with other drug substances. Amitriptyline is a very interesting drug candidate with respect to preventing and/or treating neurogenic pains and phantom pains.
The term xe2x80x9copioidxe2x80x9d is used here to designate a group of drugs that are, to varying degrees, opium- or morphine-like in their properties. The term includes natural and synthetic opioids as well as active metabolites such as morphine-6-glucuronide and morphine-3-glucuronide, and mixtures of opioids. Pharmaceutically acceptable salts and/or complexes of opioids are also within the definition of opioids.
Further relevant examples of opioids for use in compositions according to the invention include alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine, bezitramide, buprenorphine butorphanol, clonitazene, codeine, cyclazocine, desomorphine, dextromoramide, dezocine, diampromide, dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene fentanyl, heroin, hydrocondone, hydromorphone, hydroxypethidine, isomethadone, dextropropoxyphene, ketobemidone, levallorphan, levorphanol, levophenacylmorphan, lofentanil, meperidine, meptazinol, metazocine, methadone, metopon, morphine, myrophine, nalbuphine, narceine, nicormorphine, norlevorphanol, normethadone, naiorphine, normorphine, norpipanone, opium, oxycodone, oxymorphone, papaveretum, pentazocine, phenadoxone, phenomorphan, phenazocine, phenoperidine, piminodine, piritramide, propheptazine, promedol, properidine, propiram, propoxyphene, sufentanil, tilidine, tramadol, salts thereof, mixtures of any of the foregoing, mixed xcexc-agonists/antagonists, xcexc- and/or xcexa-agonists, combinations of the above, and the like.
Within the scope of the invention is of course that more than one active drug substance may be present in a composition, e.g. more than one NSAID substance and/or drug substances within the same or different therapeutic classes. Specific relevant therapeutic classes are M01A (NSAIDs), R05D, N02 (analgesics), N2A (opioids) and N2B (non-narcotic analgesics).
Dosage
In general, the dosage of the active drug substance present in a composition according to the invention depends inter alia on the specific drug substance, the age and condition of the patient and of the disease to be treated.
Compositions according to the invention will generally contain an amount of the active drug substance which enables a sufficient therapeutic and/or prophylactic response.
In order to illustrate the broad ranges of suitable doses, the recommended daily doses for selected NSAID substances is listed in the following:
Aceclofenac: 200 mg
Diclofenac: 100 mg
Etodolac: 400 mg
Fenbufen: 900 mg
Fnoprofen: 1.5 g
Flurbiprofen: 200 mg
Ibuprofen: 1.6 g
Indometacin: 100 mg
Ketoprofen: 200 mg
Meloxicam: 15 mg
Nabumeton: 1 g
Naproxen: 750 mg
Piroxicam: 20 mg
Sulindac: 300 mg
Tenoxicam: 20 mg
Tiaprofenic acid: 600 mg
Tolfenamic acid: 400 mg
Tolmetin: 800 mg
The amount of e.g. an NSAID substance in a quick release composition according to the invention may be selected so that is corresponds to about 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 8 mg, 10 mg, 12 mg, 16 mg, 20 mg, 24 mg, 25 mg, 30 mg, 32 mg, 50 mg, 60 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1 g, 1.1 g, 1.2 g, 1.3 g or 1.6 g of NSAID substance which are dosages generally known in the art.
A composition according to the invention may be produced in different series of dosage forms of e.g. 4 mg, 8 mg, 12 mg, 16 mg, 24 mg, 32 mg etc., each of the series having individual properties resulting from the design of modified release of the composition. Any desired total dosage can then be selected from the relevant dosage forms within each of the series.
The preferred dosage form according to the invention is in the form of a capsule, tablet, sachet etc. The size of the dosage form is adapted to the amount of the active drug substance contained in the composition.
The above suggested dosage amounts should not be regarded as a limitation of the scope of the invention as it is obvious for the skilled person that any desired amount of the active drug substance may be applied and is only limited by the size of the composition and the type of the active drug substance.
Pharmaceutically Acceptable Excipients
Apart from the active drug substance in the composition, a pharmaceutical composition according to the invention may further comprise pharmaceutically acceptable excipients.
In the present context, the term xe2x80x9cpharmaceutically acceptable excipientxe2x80x9d is intended to denote any material which is inert in the sense that it substantially does not have any therapeutic and/or prophylactic effect per se. A pharmaceutically acceptable excipient may be added to the active drug substance with the purpose of making it possible to obtain a pharmaceutical formulation which has acceptable technical properties. Although a pharmaceutically acceptable excipient may have some influence on the release of the active drug substance, materials useful for obtaining modified release are not included in this definition.
Fillers/diluents/binders may be incorporated such as sucrose, sorbitol, mannitbl, lactose (e.g., spray-dried lactose, xcex1-lactose, xcex2-lactose, Tabletose(copyright), various grades of Pharmatose(copyright), Microtose or Fast-Floc(copyright)), microcrystalline cellulose (e.g., various grades of Avicel(copyright), such as Avicel(copyright) PH101, Avicel(copyright) PH102 or Avicel(copyright) PH105, Elcema(copyright) P100, Emcocel(copyright), Vivacel(copyright), Ming Tai(copyright) and Solka-Floc(copyright)), hydroxypropylcellulose, L-hydroxypropylcellulose (low-substituted) (e.g. L-HPC-CH31, L-HPC-LH11, LH 22, LH 21, LH 20, LH 32, LH 31, LH30), dextrins, maltodextrins (e.g. Lodex(copyright) 5 and Lodex(copyright) 10), starches or modified starches (including potato starch, maize starch and rice starch), sodium chloride, sodium phosphate, calcium phosphate (e.g. basic calcium phosphate, calcium hydrogen phosphate), calcium sulfate, calcium carbonate. In pharmaceutical formulations according to the present invention, especially microcrystalline cellulose, L-hydroxypropylcellulose, dextrins, maltodextrins, starches and modified starches have proved to be well suited.
Disintegrants may be used such as cellulose derivatives, including microcrystalline cellulose, low-substituted hydroxypropyl cellulose (e.g. LH 22, LH 21, LH 20, LH 32, LH 31, LH30); starches, including potato starch; croscarmellose sodium (i.e. cross-linked carboxymethyicellulose sodium salt; e.g. Ac-Di-Sol(copyright)); alginic acid or alginates; insoluble polyvinylpyrrolidone (e.g. Polyvidon(copyright) CL, Polyvidon(copyright) CL-M, Kollidon(copyright) CL, Polyplasdone(copyright) XL, Polyplasdone(copyright) XL-10); sodium carboxymethyl starch (e.g. Primogel(copyright) and Explotab(copyright)).
Glidants and lubricants may be incorporated such as stearic acid, metallic stearates, talc, waxes and glycerides with high melting temperatures, colloidal silica, sodium stearyl fumarate, polyethylenglycols and alkyl sulphates.
Surfactants may be employed such as non-ionic (e.g., polysorbate 20, polysorbate 21, polysorbate 40, polysorbate 60, polysorbate 61, polysorbate 65, polysorbate 80, polysorbate 81, polysorbate 85, polysorbate 120, sorbitane monoisostearate, sorbitanmonolaurate, sorbitan monopalmitate, sorbitan monostearate, sorbitan monooleate, sorbitan sesquioleate, sorbitan trioleate, glyceryl monooleate and polyvinylalkohol), anionic (e.g., docusate sodium and sodium lauryl sulphate) and cationic (e.g., benzalkonium chloride, benzethonium chloride and cetrimide) or mixtures thereof.
Other appropriate pharmaceutically acceptable excipients may include colorants, flavouring agents, and buffering agents.
A coating may also be applied on a composition according to the invention provided that the coating does not substantially retard the release of the active drug substance from the composition. Typically, a film coating may be employed.
Manufacturing Processes
As discussed above, the invention also relates to a method for preparing a composition according to the invention. The method comprising the steps of
i) mixing the therapeutically and/or prophylactically active substance with a) an alkaline substance, b) a filler having binding properties, and, optionally, c) other pharmaceutically acceptable excipients to obtain a powder mixture,
ii) contacting the thus obtained powder mixture with an aqueous medium to obtain a wet powder,
iii) drying the thus obtained wet powder at a temperature above room temperature until the water content in the powder is at the most about 5% w/w determined as described herein, to obtain a first particulate mixture,
iv) sieving the thus obtained first particulate mixture,
v) optionally, adding any further pharmaceutically acceptable excipients to obtain a second particulate mixture,
vi) optionally, compressing the thus obtained second particulate mixture into tablets, and
vii) optionally, coating the thus obtained tablets.
The individual steps of the method are performed in apparatus which are suitable for the specific type of process step. It is of course advantageous to performed more than one step in the same apparatus provided that the critical conditions can be controlled in the desired manner.
With respect to step i), the most critical parameter is the particle size of the starting material, cf. the discussion above, especially the particle size of the filler having binding properties.
Step ii) is a very important step and the conditions under which this step is carried out are very critical. Most important is it that in this step the powder is subjected to not a granulation process but a wetting process resulting in a particulate material in which the individual particles of the powder mixture are brought into contact and held together by binding forces which are established by the energy input given during step ii) The present inventors have made investigations which show that A) if a normal granulation process is employed, i.e. a process which results in the formation of agglomerates, or B) if a direct compression (see Example 20b) procedure is employed, i.e. a process in which step ii) is irrelevant because no wetting of the powder blend takes place, then the final composition does not fulfil the requirements with respect to quick release. However, as reported in the experimental section herein the use of the correct conditions may lead to a composition from which almost 100% w/w of the active substance (at least 90-95% w/w) is released in vitro within the first 10 min of the test employing Dissolution method I as described below.
The mechanism which is believed to take place in step ii) is to bring the active substance and the alkaline substance in close contact and at the same time utilise conditions which are favourable with respect to building up a composition which has optimal disintegration and dissolution properties. To this end, it is believed that employment of an alkaline substance which is able to produce gas, carbon dioxide, upon contact with water (or an aqueous medium having a pH below 7) is acceptable as a certain production of gas during the wetting procedure facilitates the necessary controlled disintegration of the final compostion, i.e. avoiding a too fast disintegration due to an excessive amount of gas production when the final composition disintegrates. To this end, the inventors have performed experiments in which the active substance and the alkaline substance have been subjected to a treatment with an aqueous medium and subsequently dried and then the particulate material obtained in this manner has been employed in step i) of the method described above. However, this procedure does not lead to a satisfactory result and the composition obtained has a unacceptable shelf-life, i.e. the aqueous pre-treatment of the active substance with the alkaline substance seems to have a negative influence on the chemical stability of the active substance itself.
The critical parameters in step ii) are the contact medium, the contact time and the energy input (i.e. the energy added to the powder mixture to build up the particulate material). The particle size of the resulting particulate material is a very important parameter, cf. the discussion above, but as mentioned above it is possible successfully to obtain suitable composition even if the particle size of the particulate material is larger than the sizes claimed if the particles either are soft or have an increased porosity.
The contact medium is not used as a granulation medium, e.g. no water-soluble binders is present in the medium. Typically the medium is an aqueous medium having a composition as described hereinbefore. A preferred medium is a medium containing ethanol and water and wherein the concentration of ethanol in the solvent is from about 0% v/v to about 95% v/v such as, e.g., from about 10% v/v to about 90% v/v, from about 10% v/v to about 80% v/v, from about 15% v/v to about 70% v/v, from about 15% v/v to about 60% v/v, from about 20% v/v to about 50% v/v, from about 20% v/v to about 40% v/v, from about 25% v/v to about 35% v/v such as, e.g. about 33.3% v/v. An especially suitable aqueous medium is a medium containing ethanol and water in a volume ratio of from about 1:10 to about 1:1 such as from about 1:3 to about 1:1.5, e.g. 1:2.
With respect to the energy supply during step ii) the present inventors have found that the use of a mixer of the type high speed impeller is suitable.
The energy supplied during step ii) may advantageously be added discontinuous, i.e. with intervals of wet-massing and wet-resting (i.e. intervals in which the aqueous medium is added to the powder during mixing and intervals in which no adding of aqueous medium takes place and no mixing takes place as exemplified in Example 16).
As a starting point of determining the necessary energy supply when either changing the batch size or the apparatus, the swept volume is a guidance.
The swept volume is related to the energy input and is defined in the following way:
The vertical swept volume out by one impeller blade at each revolution is calculated by dividing the blade area into vertical segments. Based on this volume and the impeller speed, the volume swept out by the blades per second is determined relative to the volume of the product or the volume of the bowl.
Moreover, it is important that step ii) is performed in a suitable apparatus which enables an energy input which a) is sufficient to bringing the particles in contact with the aqueous medium without substantially deteriorate the stability of the final composition and/or b) is sufficient to bringing the therapeutically and/or prophylactically active substance and the alkaline substance in contact with the aqueous medium without negatively influencing the release rate of the active substance from the final composition.
As discussed above, step ii) is typically performed in a conventional high shear mixer employing an energy input which is sufficient to enable a contact to take place between the therapeutically and/or prophylactically active substance and the alkaline substance employed in step i) but at the same time is sufficiently low to avoid formation of a large amount of agglomerates during the mixing.
The mean particle size of the particles of the first particulate mixture is at the most about 100% larger than the mean particle size of the powder mixture from step i) before subjecting the powder mixture to the reaction in the aqueous medium employed in step ii).
More specifically, the mean particle size of the particle of the first particulate mixture is at the most 90% such as, e.g., about 80%, about 75%, about 70%, about 65%, about 60%, about 55% or about 50% larger than the mean particle size of the powder mixture from step i) before subjecting the powder mixture to the reaction in an aqueous medium employed in step ii).
The particle size is also expressed by results of a sieve analysis and then the following sizes are relevant:
The powder obtained in step i) has such a particle size thatxe2x80x94when the powder is subjected to a sieve analysisxe2x80x94then at least about 90% w/w such as, e.g. at least about 92% w/w, at least about 94% w/w, at least about 95% w/w, at least about 96% w/w, at least about 97% w/w, at least about 97% w/w, at least about 98% w/w or at least about 99% w/w of the particles passes through sieve 180 xcexcm, and the first particulate mixture obtained in step iii) has such a particle size thatxe2x80x94when the particulate composition is subjected to a sieve analysisxe2x80x94then at least about 50% w/w such as, e.g., at least about 55% w/w, at least about 60% w/w, at least about 65% w/w, at least about 70% w/w, at least about 75% w/w, at least about 80% w/w, at least about 85% w/w, at least about 90% w/w or at least about 95% w/w of the particles passes through sieve 180 xcexcm.
Typically, the mean particle size of the particles of the first particulate mixture is at the most about 250 xcexcm, such as, e.g. at the most about 240 xcexcm, at the most about 230 xcexcm, at the most about 220 xcexcm, at the most about 210 xcexcm, at the most about 200 xcexcm, at the most about 190 xcexcm, at the most about 180 xcexcm, at the most about 175 xcexcm, at the most about 150 xcexcm, at the most about 125 xcexcm, at the most about 100 xcexcm, at the most about 90 xcexcm, at the most about 80 xcexcm or at the most about 75 xcexcm.
Step iii) in which the wet particulate material is dried is of course also important in order to obtain a proper shelf-life of the product. The remaining steps are steps well known in the art of pharmaceutical formulation and a person skilled in the art knows hand-books in which further details are found.